This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis C virus (HCV)-induced chronic liver disease with associated cirrhosis and hepatocellular carcinoma is now the leading indication for liver transplantation in the United States. And while blood donor screening has reduced new transfusion-acquired HCV infections in industrialized nations to a negligible level, new cases continue to occur as a result of intravenous drug use or accidental needlestick exposures. There are currently an estimated 170 million HCV carriers worldwide and nearly 3 million in the U.S. (~2% of the population). The persistence of HCV infection continues to contribute to its increasing prevalence and potentially grave clinical consequences. Unfortunately, there is not a vaccine to prevent HCV infection and the only licensed therapy for chronic HCV infection is expensive, associated with poor response rates, and laden with significant side effects. However, 20% of people who are infected with HCV are mysteriously able to naturally clear the infection. Our work is designed to identify the defect in the host immune response responsible for the inability of the remaining 80% to naturally clear HCV infection. We hypothesized that the cellular immune response is the principal determinant of whether HCV infection is acutely resolved or establishes persistence and we are seeking to elucidate and understand the essential components of an effective anti-HCV immune response. We are utilizing a large cohort of chronically infected human patients, as well as novel cell culture systems to dissect the anti-HCV immune response. We have identified phenotypic markers of anti-HCV liver infiltrating T cells that correlate with T cell dysfunction that may be targets for immune augmentation. We have also described an increased propensity of HCV specific cells to undergo massive apoptosis in the peripheral blood during acute infection and in the liver during chronic infection.